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Pegylated Lacritin N-104 Promotes Mouse Islet Stabilization and Prevents Diabetes Progression in the Non-Obese Diabetic (NOD) Mouse Model

M. Ma1, P. Chhabra1, G. Laurie2, K. L. Brayman1

1Department of Surgery, University of Virginia Health System, Charlottesville, VA, 2Department of Cell Biology, University of Virginia Health System, Charlottesville, VA

Meeting: 2022 American Transplant Congress

Abstract number: 637

Keywords: Graft survival, Islets, Peptides, Proliferation

Topic: Basic Science » Basic Science » 06 - Tissue Engineering and Regenerative Medicine

Session Information

Session Name: Tissue Engineering and Regenerative Medicine

Session Type: Poster Abstract

Date: Saturday, June 4, 2022

Session Time: 5:30pm-7:00pm

 Presentation Time: 5:30pm-7:00pm

Location: Hynes Halls C & D

*Purpose: To investigate if PEGylated Lacritin N-104 (PEG N-104) prevents the progression of type 1 diabetes (T1D) in the NOD mouse.

*Background: Lacritin is a multifunctional protein in human tears with prosecretory, prosurvival, and mitogenic properties. Lacritin N-104, an NFAT and mTOR agonist, promotes islet viability, insulin secretion, and graft survival following islet transplantation. Polyethylene glycol (PEG) extends the peptide’s half-life by increasing its size and making the surface less sensitive to proteolysis.

*Methods: a) Lacritin and its analogs were PEGylated at the N- or C-terminus. Mouse islets were treated with 4uM PEGylated N-94 or C-95, positive control N-104, or negative control C-95 for 24 hours in DMEM at 37°C. These islets were used in glucose-stimulated insulin secretion (GSIS) assay. Viability of islets was also scored by propidium iodide – fluorescein diacetate staining; and b) PEG N-104 was injected subcutaneously (SQ) or N-104 was injected intraperitoneal (IP) to 9-weeks old NOD mice, thrice a week until they were 16-weeks old. Tail vein blood glucose was measured daily.

*Results: Mouse islets treated with 4uM PEGylated N-94 or C-95, N-104, or C-95 were used in GSIS assay. N-94 activity was superior when N-terminus was PEGylated, GSIS being 1.6-fold high compared to untreated islets. GSIS with both free N-104 and N-terminus PEG N-104 was 2-fold higher compared to the untreated group and the negative control C-95 group. In NOD mice, PEG N-104 (SQ) or free N-104 (IP) completely prevented the development of T1D at week 18 (n=5). In contrast, neither SQ or IP injected C-95 (n=5) nor saline (n=5) could delay the progression of T1D, as 100% of mice became diabetic by SQ injection of C-95 or saline, and 60% became diabetic by IP injection of C-95. Moreover, both PEG N-104 and free N-104, injected at 20, 40, or 80 μM concentrations, completely prevented T1D progression in NOD mice as indicated by blood glucose (BG) below 200 mg/dL. BG was measured until mice were 26-weeks old. No stomach bloating or weight loss was observed in these mice.

*Conclusions: Our data indicates N-terminus PEGylation of N-104 could extend the peptide’s half-life without inhibiting its abilities to promote islet function. In addition, systemic administration of free N-104 or PEG-N-104 by SQ or IP injection could prevent the progression of T1D in NOD mice.

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To cite this abstract in AMA style:

Ma M, Chhabra P, Laurie G, Brayman KL. Pegylated Lacritin N-104 Promotes Mouse Islet Stabilization and Prevents Diabetes Progression in the Non-Obese Diabetic (NOD) Mouse Model [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/pegylated-lacritin-n-104-promotes-mouse-islet-stabilization-and-prevents-diabetes-progression-in-the-non-obese-diabetic-nod-mouse-model/. Accessed March 26, 2023.

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